Pain control is necessary for successful rehabilitation and outcome after total knee arthroplasty. Our goal was to compare the clinical efficacy of periarticular injections consisting of a long-acting local anesthetic (ropivacaine) and epinephrine with and without combinations of an α2-adrenergic agonist (clonidine) and/or a nonsteroidal anti-inflammatory agent (ketorolac). In a double-blinded controlled study, we randomized 160 patients undergoing total knee arthroplasty to receive 1 of 4 intraoperative periarticular injections: Group A, ropivacaine, epinephrine, ketorolac, and clonidine; Group B, ropivacaine, epinephrine, and ketorolac; Group C, ropivacaine, epinephrine, and clonidine; Group D (control), ropivacaine and epinephrine. Compared with Group D, Group A and B patients had significantly lower postoperative visual analog pain scores and nurse pain assessment and Group C patients had a significantly greater reduction in physical therapist pain assessment. We found no differences in other parameters analyzed.